PROBLEM: Aging is the single most important risk factor for Alzheimer's disease (AD), which represents the most common cause of dementia in the World. The disease preferentially affects individuals who are older than 65 years of age and is becoming increasingly prevalent among our aging veteran population. PRELIMINARY DATA: In the Preliminary Studies section, we show that p75NTR and ceramide are required for the age-associated activation of A( generation. We also show that hyperactivation of the aging program (mediated by the insulin-like growth factor 1 receptor, IGF1-R) in p44+/+ transgenic mice, a model of accelerated aging, leads to early TrkA-to-p75NTRswitch, increased production of A(, tau hyperphosphorylation, and memory impairment. The above events were linked to overproduction of ceramide and molecular stabilization of BACE1. When engineered to express APP695/swe, p44+/+ mice developed a severe form of AD-like neuropathology and early death. It is worth stressing that the hyperactivation of IGF1-R signaling displayed by p44+/+ mice is a consequence of the marked down-regulation of PTEN produced by the p44 transgene. This is particularly important because AD brains are also characterized by decreased levels of PTEN, hyperactivation of IGF1-R signaling, increased expression/activity of p75NTR, and increased levels of ceramide. These similarities strengthen the relevance of the p44+/+ model for the study of AD pathology. Finally, we also report the successful identification of p75SMI, a molecular interactor responsible for the p75NTR-dependent activation of nSMase. HYPOTHESIS: The central hypothesis of this proposal is that the p75NTR-ceramide signaling system plays an important role in the pathogenesis and progression of AD neuropathology, and represents a potential therapeutic target for the prevention of this terrible disease. STUDY DESIGN: Specific Aim 1 will analyze the effects produced by the hyperactivation of p75NTR- ceramide signaling on the course and development of AD pathology in p44+/+;APP695/swe mice. To address this objective, we have described a battery of biochemical, histological, and cognitive approaches. In addition, we will also treat p44+/+;APP695/swe animals with manumycin A to assess whether this is an effective strategy to block/delay all the aspects of the neuropathology. Finally, we will analyze how the aging program affects tau metabolism and the learning/cognitive functions of the mice. Specific Aim 2 will analyze the role of p75SMI, which is required for the p75NTR-mediated activation of ceramide. To address the above objectives, we described a combination of biochemical, cellular, and genetic approaches in both primary neurons and neuronal cell lines. The biochemical approaches include in vitro assays, in vitro affinity binding, IP/co-IP studies, and pharmacological inhibitors, whereas the genetic approaches include mutant neuronal cell lines, deletion mutant clones of p75NTR, antisense oligonucleotides, siRNA, and deletion mutants of p75SMI. PUBLIC HEALTH RELEVANCE: Narrative (Relevance Statement) POTENTIAL IMPACT ON VETERANS' HEALTH CARE: Our studies have uncovered a novel molecular link between aging and AD, and are leading the field toward new directions that, if successful, will have direct impact on the prevention of a disease that is projected to affect nearly 15 million Americans by the year 2050. This particular project is important for our understanding of basic molecular events that characterize both normal aging of the brain and AD neuropathology. It has direct relevance for the research and clinical priorities of the Dept. of Veterans Affairs, and will have impact on our abilities to increase basic knowledge of aging, to respond to the dramatic rise of age-associated pathologies among the aging veteran population, and to improve the quality of care to the aged. Finally, the long-term goal of this project is consistent with the mission of the Geriatric Research, Education and Clinical Center (GRECC) of this VA Hospital.